Since osteoporosis is most common in postmenopausal women, most of the definitive studies have examined its epidemiology, pathogenesis, diagnosis, and treatment in this older population. Osteoporosis is diagnosed much less frequently in premenopausal women. In a substantial proportion of premenopausal women with osteoporosis, a secondary cause, such as glucocorticoid excess, celiac disease, or anorexia nervosa, is found. Identification of the contributing condition helps to guide clinical management. However, some young women with osteoporosis do not have a definable cause, and are said to have idiopathic osteoporosis (IOP). In these young women, there is very little information currently available on etiology or therapy. The goal of this research proposal is to characterize the osteoporotic bone disorder in otherwise healthy premenopausal women who present with low-trauma fractures, and who do not have a known underlying cause. Affected women will be compared to normal women in a cross-sectional, case-control study. Clinical, biochemical, hormonal, densitometric, radiographic, and histomorphometric analyses will be utilized to define differences between cases and control subjects. Central to this proposal is our hypothesis that IOP in premenopausal women is a disorder of bone quality. To test this hypothesis, we will use state-of-the-art tools to measure key elements of bone quality, including bone turnover, geometry, microarchitecture, and material properties. Noninvasive techniques such as central quantitative computed tomography and ultrahigh resolution peripheral quantitative computed tomography, a very new approach, will be used to determine bone geometry, cortical and trabecular bone structure and connectivity. A percutaneous bone biopsy will be obtained and analyzed by quantitative static and dynamic histomorphometry. In addition, newer biopsy analytic techniques will be utilized to determine the 3-dimensional structure and strength of bone and material properties of bone mineral and matrix. This characterization of the disorder of IOP in young women is an essential first step towards the development of targeted treatment strategies for those affected by this condition. In addition, this project will allow me to receive mentorship and training as part of a 5-year career development plan. I will thus acquire the technical and interpretive skills in the assessment of bone quality that will be necessary for my career as an independent investigator in the field of metabolic bone diseases.